Pipette/applicator

ABSTRACT

A liquid agent applicator including a collapsible reservoir for storing the liquid agent, and a shaft having a lumen there through connected to the collapsible reservoir. The liquid agent applicator also includes an opening mechanism that is inserted into an orifice in one end of said shaft. The liquid agent applicator being sealed by a breakable seal formed between the opening mechanism and the shaft, wherein twisting of the opening mechanism relative to the shaft breaks the seal allowing egress of the liquid agent stored in the reservoir.

INCORPORATION BY REFERENCE

Each document cited in this text (“application cited documents”) and each document cited or referenced in each of the application cited documents, and any manufacturer's specifications or instructions for any products mentioned in this text and in any document incorporated into this text, are hereby incorporated herein by reference; and, technology in each of the documents incorporated herein by reference can be used in the practice of this invention. In addition, commonly assigned design patent application of PATRICE WURTZ and SUSAN LIEBENGUTH concurrently filed herewith titled “PIPETTE/APPLICATOR and OPTIONAL TOPS THEREFOR” (Attorney Docket No. MER 04-030) is hereby incorporated by reference.

It is noted that in this disclosure, terms such as “comprises”, “comprised”, “comprising”, “contains”, “containing” and the like can have the meaning attributed to them in U.S. patent law; e.g., they can mean “includes”, “included”, “including” and the like. Terms such as “consisting essentially of” and “consists essentially of ” have the meaning attributed to them in U.S. patent law, e.g., they allow for the inclusion of additional ingredients or steps that do not detract from the novel or basic characteristics of the invention, i.e., they exclude additional unrecited ingredients or steps that detract from novel or basic characteristics of the invention, and they exclude ingredients or steps of the prior art, such as documents in the art that are cited herein or are incorporated by reference herein, especially as it is a goal of this document to define embodiments that are patentable, e.g., novel, nonobvious, inventive, over the prior art, e.g., over documents cited herein or incorporated by reference herein. And, the terms “consists of” and “consisting of” have the meaning ascribed to them in U.S. patent law; namely, that these terms are closed ended.

FIELD OF THE INVENTION

The present invention is directed to a new and useful apparatus for dispensing liquid agents. Specifically, the present invention is directed to an apparatus for applying liquids to the skin of an animal for the prevention and treatment of disease or parasite infestation.

BACKGROUND OF THE INVENTION

There are known in the prior art a variety of devices for the application of liquids onto the skin of animals. One well known device is a syringe. A syringe includes a body in which the liquid is stored, a plunger that forces the liquid out of the body, and a needle or applicator tip for accurately locating the point of application of the liquid. While such a device is well suited for injection of liquids into the body, it is not well suited for topical application. One obvious drawback of this device in the topical application situation is the apparent danger of puncturing the skin of the animal or the person applying the liquid when using a syringe with a needle. Many liquid agents, which are intended for topical use can have harmful or irritating reactions when applied beneath the skin of the animal. For at least this reason, the use of syringes is best left to the trained professional, particularly when one considers the strength and agility of an animal such as a large dog and its desire to flee. In addition, although having a seemingly small cost, these devices in fact quite expensive in comparison to other alternative topical application devices. Accordingly, they are not a good alternative for use in inexpensive single use applications.

Another device, which has come into some prominence lately, particularly in the application of topical flea and tick preventative agents, is a type of plastic pipette. One common device 50, shown in FIG. 2, comprises a storage chamber 52 formed of a flexible plastic material 56 and a semi or substantially rigid material 54. The device further comprises, a narrowed neck 58, and a break away tip 60. Flexible materials typically have a thickness below about 100 μm and include for example polyesters, polyamides, polypropylenes, polyolefins, and aluminum foils. Preferably, the aluminium foils have a thickness of less than about 20 μm. Rigid materials typically have a thickness of below about 200 μm and include for example, polyethylene terephthalate (PET), amorphous polyethylene terephthalate (APET), polyethylene terephthalate glycol (PETG), or crystalline polyethylene terephthalate (CPET), polyvinyl chloride (PVC), polypropylene (PP), cycloolefin copolymers such as that known under the tradename COC®, poly acrilo nitrile (PAN) such as that known under the tradename BAREX®, fluropolymer or chlorotrifluoroetheylene (CTFE) such as that known under the tradename ACLAR®, and aluminum foils up to about 100 μm. In use, the tip 60 of the pipette 50 is broken off to allow for the free flow of the liquid agent from the storage chamber 52 to the skin of the animal via the neck 58. Once the tip 60 is broken off, the pipette 50 is arranged on the animal so that the neck 58 of the pipette parts the animals hair, and the storage chamber 52 is squeezed to compress the flexible material 56 against the rigid material 54 and force the liquid agent through the neck 58, and onto the skin of the animal.

This device, however, has several drawbacks. The first of these is that the break away tip 60 can be difficult to break due to the use of the rigid materials discussed above. A struggle with the tip, by the user, can sometimes result in the undesirable release of the liquid agent onto the user. Many of the agents, particularly anti-flea and tick agents, can be very irritating when inadvertently applied to human skin, and pose an even greater danger if inadvertently splashed into the eyes or mouth of the user. In addition, these break away tips typically require the use of two hands to open before the user can apply the liquid to the animal.

In addition, because of the use of separate materials, (e.g. flexible and rigid) further difficulties are created. One of these is that the tip 60 may remain attached to the pipette 50 after breaking. This can lead to an inability for the user to penetrate the animal's fur after opening. Naturally, since these medications are to be absorbed through the skin, the failure to apply them directly onto the skin poses dosing problems.

Yet another drawback, of the prior art device, is that when the tip is broken off, a sharp edge may be formed on the end of the neck by the severed end of the rigid material 54. This edge can be sharp enough to injure either the animal or the user. Application of the liquid agent to an animal or user that has been cut by the sharp edge can be very irritating.

Accordingly, there is a need for a liquid agent applicator that is easy to open without potential for spraying the user, that ensures the liquid agent application to the skin and beneath the hair of the animal, and that does not retain a sharp edge after opening.

SUMMARY OF THE INVENTION

It is one advantageous embodiment of the present invention to produce a liquid agent applicator that is safe for both the user and an animal receiving treatment.

It is another advantageous embodiment of the present invention produce a liquid agent applicator that can be opened by a user single-handedly, does not have a likelihood of splashing the user with the liquid agent, and does not produce a sharp edge upon opening.

It is yet another advantageous embodiment of the present invention to produce a liquid agent applicator that can be placed in an upright position after opening.

It is yet another advantageous embodiment of the present invention to produce a liquid agent applicator that is child resistant.

Accordingly, a liquid agent applicator is described having a collapsible reservoir for storing the liquid agent and a shaft having a lumen there through connected to the collapsible reservoir. The liquid agent applicator includes an opening mechanism inserted into an orifice formed in one end of the shaft and a breakable seal formed between the opening mechanism and the shaft. Further, twisting of the opening mechanism relative to the shaft breaks the seal allowing egress of the liquid agent stored in the reservoir.

In another embodiment, the liquid applicator includes a child resistant opening mechanism. The child resistant opening mechanism includes a rigid stationary neck and a movable cap. The child resistant opening mechanism also includes a septum for preventing the egress of liquid from the reservoir formed on the stationary neck, and a punch formed on the movable cap, for piercing the septum to allow the egress of liquid from the reservoir. The child resistant opening mechanism also includes an interlock requiring two or more movements of the movable cap by the user, wherein upon completion of the two or more actions, the movable cap is movable along the stationary neck in the direction of the septum. And movement of the stationary cover in the direction of the septum causes the punch to pierce the septum and release the liquid agent.

These and other embodiments are disclosed or are obvious from and encompassed by, the following Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following Detailed Description, given to describe the invention by way of example, but not intended to limit the invention to specific embodiments described, may be understood in conjunction with the accompanying Figures, incorporated herein by reference, in which:

FIG. 1 is a perspective view of a liquid applicator according to the present invention;

FIG. 2 a is a front view of a prior art pipette;

FIG. 2 b is a side view of a prior art pipette;

FIG. 3 a is a cross-sectional view of a shaft of a pipette according to one embodiment of the present invention;

FIG. 3 b is a cross sectional view of a shaft of a pipette according to another embodiment of the present invention.

FIG. 4 is a cross-sectional view of a CR shaft according to one embodiment of the present invention; and

FIG. 5 is side view of a CR shaft according to one embodiment of the present invention.

FIG. 6 is a perspective view of a liquid applicator with a CR shaft.

FIG. 7 is a perspective view of three examples of one embodiment of the present invention as formed by a thermoforming process.

FIG. 8 is a front view of three examples of one embodiment of the present invention as formed by a thermoforming process.

DETAILED DESCRIPTION

A pipette according to the present invention is shown if FIG. 1. As can be seen by reference to FIG. 1, the pipette 10 includes a base or reservoir 12, connected to a shaft 14, and an opening mechanism 16. The shaft 14 has a lumen 24 extending there through fluidly connected to the reservoir 12. The pipette 10 is designed for easy, no-mess, one-handed use.

The base or reservoir 12 is advantageously formed with finger grips or notches 18 formed therein to assist the user in grasping the pipette 10. These grips 18 allow the pipette to be held by the user with only two fingers, and further enable the user to apply pressure to the reservoir 12, of the pipette 10, for application of the liquid stored therein using just these two fingers. Accordingly, the grips 18 assist the user by providing means for safe and effective one handed holding and use of the pipette 10.

The reservoir 12 is advantageously shaped with a substantially flat or slightly concave bottom 20, which enables the pipette 10 to be placed in an upright position on a flat surface such as a table or counter. The bottom 20 represents a considerable advantage to the user in that he/she can open the pipette 10 and place it down without fear that the contents of the pipette will spill out. Particularly in use with animals and more particularly in the application of anti-flea and tick liquids such a feature is particularly useful. Often after opening a pipette there may be reason for the pipette to be place down on a table or counter. These reasons can include the need to reposition the animal or the user's grip on the animal, or simply being finished with application before disposal of the pipette. Previously known pipettes used for such applications were formed with a base that did not allow for upright placement of the pipette, as shown in FIG. 2. Accordingly, any post-opening placement of the pipette on a flat surface was likely to result in spillage of the liquid contained therein. As many of these liquids can cause reactions when they come in contact with human skin the prevention of such a spillage represents a substantial benefit to the user.

The reservoir 12 is formed of a collapsible material that allows the user to apply pressure to the finger grips with just two fingers of one hand and force the fluid contained in the reservoir through the shaft 14. However, in one advantageous embodiment, the reservoir 12 is formed of a material having sufficient rigidity that initial grasping of the reservoir 12 by the user will not compress the reservoir 12 sufficiently to cause the liquid agent to be expelled from the orifice of the shaft 14. To propel the liquid agent from the reservoir 12 through the shaft 14 and out the orifice, requires an appreciable but not undue amount of force in excess of that required to grasp and hold the pipette 10. One of skill in the art will understand that a variety of suitable plastic materials may be used to form the pipette 10. Further these plastic materials may be formed as a single or monolayer, alternatively the plastic materials may be formed as a lamination of multiple plastic layers without departing from the scope of the present invention.

Another feature of the pipette 10 that aids in the ease of one-handed use is the opening mechanism 16, as shown in FIG. 3. The opening mechanism 16 is formed so that twisting will remove it from the shaft 14. In one embodiment, the opening mechanism 16 may be threaded like a bolt into the lumen 24 of the shaft 14. In this embodiment, threads are formed on both the interior of the shaft, and the exterior of a plug 30 of the opening mechanism 16. Alternatively, the plug 30 may simply be inserted into the orifice formed at the end of the lumen 24 in the shaft 14 with sufficient force to prevent express of the fluid without removal of the plug. Twisting of the opening mechanism 16 allows the user to extract the plug 30 from the lumen 24.

In a further embodiment shown in FIG. 3 b, a plastic seal 25 can be formed between the plug 30 and the shaft 14, preventing the egress of liquid out of the pipette 10. The seal 25 maybe formed, for example, of a narrowed thickness of plastic material. The plastic material of the seal 25 may be formed so that twisting of the opening mechanism 16 will overcome the tensile strength of the material causing it to shear, thereby breaking the seal. Once the seal 25 is broken, the plug 30 can be removed from the shaft 14 and an orifice is created in the shaft 14, which allows for dispensation of the fluid agent from the pipette 10. In one advantageous embodiment, the seal 25 is formed of the same plastic material as the plug 30 and the shaft 14.

In any event, opening mechanism 16 is grasped by as few as two of the user's fingers, while the pipette 10 rests in the palm of the user's hand. By application of a rotational force to the opening mechanism 16 by the user's two or more fingers, the pipette 10 is opened one-handed. Enabling one-handed opening of the pipette simplifies the application of fluids such as flea and tick repellants to dogs and cats. One problem with pipettes currently used in such applications, as shown in FIG. 2, is that they, typically require two hands to open. This in turn may require a second person to assist in holding the animal while the user opens the pipette. Alternatively, a user may attempt to hold the animal between their knees while opening the pipette. Particularly with the very large and very small animals this can present dangers to both the animal and the user. Accordingly, by providing a pipette 10 that can be opened with a single hand, the user's second hand is free to hold the animal for application, eliminating the need for a second person and removing many of the dangers to both animal and user that other means of restraint can pose.

Another advantage of the twist top opening mechanism 16 is that it prevents the formation of a sharp edge at the tip 22 of the shaft 14. As discussed above, use of many of the prior art devices resulted in the formation of a sharp plastic edge that could injure the animal during application. As many of the topical use liquid agents can be very irritating if administered into the skin of the animal or the user, the likelihood of scratching the skin presents a problem for the user and the animal. In one embodiment discussed above, the sealing of the shaft 14 of the pipette 10 to the plug 30 is accomplished using the plastic materials of the plug 30 and the shaft 14 to form a seal. The seal has a reduced tensile strength in comparison to the plug 30 and the shaft 14 that can be sheared when the opening mechanism 16 is twisted. A further feature of this embodiment is that the seal may be formed in the lumen 24. As can be readily understood, the placement of the seal at the tip 22 of the shaft 14 may not necessarily result in the prevention of a sharp edge forming on the tip 22 upon the removal of the opening mechanism 16 from the shaft 14. Accordingly, by forming the seal between the shaft 14 and the plug 30 of the opening mechanism 16 inside the lumen 24, no sharp edge will be formed on the tip 22. As a result the dangers associated with such a sharp edge are greatly reduced and there is little likelihood of injury to either the user or the animal.

The shaft 14 of the pipette 10 is advantageously formed of a substantially rigid material that resists bending. The shaft 14 is also formed with a long neck to assist in proper dosing. The long neck and resistance to bending provide beneficial support for the pipette 10 during application of the fluid agent on the animal. In particular, the stiffness or resistance to bending and the long neck allow the user to easily part the animal's hair or fur for application directly on the animals skin. In one advantageous example of the invention, the shaft 14 is between 1 and 5 cm in length.

As discussed previously, one of the major failings of some pipettes of the prior art is that the break away tip 60, as shown in FIGS. 2 a and b, tends to remain connected to the pipette which further frustrates proper dosing. In certain circumstances this could result in the animal receiving insufficient treatment and thereby compromise the effectiveness of the treatment regimen. Accordingly, the present invention provides for superior application and greater guarantees of proper dosing of the animal. One skilled in the art will readily appreciate that a variety of materials could be used to produce a shaft 14 having the proper stiffness and flexibility as described above, accordingly such materials are considered within the scope of the present invention.

Another embodiment of the present invention is a child resistant or CR shaft 44, for use with the pipette 10. The CR shaft 44 includes a rigid stationary neck 45, a movable cap 48, and a septum 46. The septum 46 acts as a seal on the pipette 10 preventing the egress of a liquid agent contained therein. The movable cap 48 includes a punch 49. The punch 49 includes a piercing tip of sufficient rigidity to allow the punch 49 to pierce the septum 46. The piercing of the septum 46 allows for the free flow of the liquid agent from the reservoir 12 of the pipette 10 to the CR shaft, 44. After piercing of the septum 46, the cap 48 is removed and the liquid is able to flow from the pipette 10. The CR shaft 44 also includes a means for preventing a child from opening the pipette 10. This means for preventing a child from opening the pipette 10 may be of a type know in the art. For example, the prevention means can include requiring depression or extension of the movable cap 48 vertically to a first position and twisting of the cover while in this first position to a rotational stop point. Once the rotational stop point is reached depression of the movable cap 48 allows the punch 49 to pierce the septum 46. After removal of the cap 48 from the CR shaft 44, the piercing of the septum 46 allows fluid communication of the liquid agent in the pipette 10 through the lumen and onto the animal. Other means of preventing a child from opening the pipette 10 will be known to those of skill in the art and are therefore considered within the scope of the present invention.

In a further embodiment, the cap 48 may include a lumen (not shown) which extends through the punch 49. This allows for egress of fluid from the pipette 10 after piercing of the septum 46.

One method of manufacturing such a pipette 10 is called thermoforming. In the thermoforming process, sheets of a desired plastic material are fed into a press. These sheets may be formed of one or more layers of plastic material. The press contains a mold of the shape to be formed for example, the reservoir 12 of the pipette 10. By heating the plastic sheets, and applying air pressure to the area between the sheets of plastic the reservoir 12 is formed. The air pressure forces a portion of the now heated plastic sheets into the molds to form the shape of the reservoir 12. In addition, the heat acts to seal the two sheets of plastic material together to form a single plastic sheet having a reservoir 12. The heat is removed, and upon cooling, reservoir 12 may be cut from the plastic sheet. FIGS. 7 and 8 show three examples of the present invention formed by a thermoforming process.

After formation, the reservoir 12 can then be filled with the desired liquid agent, for example a flea and tick repellant for use with domestic animals such as dogs and cats. After filling, the shaft 14 with opening mechanism 16 is inserted into an opening in the reservoir 12. Further application of heat to the opening in the reservoir 12 acts to seal the reservoir 12 to the shaft 14, thereby creating a sealed pipette 10 which can then be cut from the sheet of plastic for packaging and sale.

In other embodiments, the base 12 is formed and the shaft 14 inserted therein. After application of heat to the base 12 and shaft 14 combination, the liquid agent is added via an orifice in the end of the shaft 14. After filling the opening mechanism 16 is inserted into the orifice. Application of yet another source of heat seals the opening mechanism 16 to the shaft 14.

Formulations for Use with the Applicator

Any liquid agent may be stored and administered to the animal or human by this applicator. Preferred liquid agents are topical pharmaceutical or veterinary formulations. Therapeutic agents, which are present in the formulations, include, for example, substances or combination of substance such as, for example, antiviral, antibacterial, antiparasitic, antifungal substances and combinations thereof. The therapeutic agent may further be a substance, capable of acting as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like. Examples of these therapeutic agents include, but are not limited to: Anti-inflammatory agents such as hydrocortisone, prednisone, fludrotisone, triamcinolone, dexamethasone, betamethasone and the like. Anti-bacterial agents such as penicillins, cephalosporins, vancomycin, bacitracin, polymycins, tetracyclines, chloramphenicol, erythromycin, streptomycin, and the like. Antiparasitic agents such, as quinacrine, chloroquine, quinine, and the like. Antifungal agents such as nystatin, gentamicin, miconazole, tolnaftate, undecyclic acid and its salts, and the like. Antiviral agents such as vidarabine, acyclovir, ribarivin, amantadine hydrochloride, iododeoxyuridine, dideoxyuridine, interferons and the like. Antineoplastic agents such as methotrexate, 5-fluorouracil, bleomycin, tumor necrosis factor, tumor specific antibodies conjugated to toxins, and the like. Analgesic agents such as salicylic acid, salicylate esters and salts, acetaminophen, ibuprofen, morphine, phenylbutazone, indomethacin, sulindac, tolmetin, zomepirac, and the like. Local anaesthetics such as cocaine, benzocaine, novocaine, lidocaine, and the like. Vaccines, or antigens, epitopes, immunogens of human or animal pathogens, such as hepatitis, influenza, measles, mumps, rubella, hemophilus, diphtheria, tetanus, rabies, polio, as well as veterinary vaccines and the like. Central nervous system agents such as tranquilizers, sedatives, anti-depressants, hypnotics, β-adrenergic blocking agents, dopamine, and the like. Growth factors such as colony stimulating factor, epidermal growth factor, erythropoietin, fibroblast growth factor, neural growth factor, human growth hormone, platelet derived growth factor, insulin-like growth factor, and the like. Hormones such as progesterone, estrogen, testosterone, follicle stimulating hormone, chorionic gonadotrophin, insulin, endorphins, somatotropins and the like. Antihistamines such as diphenhydramine, chlorpheneramine, chlorcyclizine, promethazine, cimetidine, terfenadine, and the like. Cardiovascular agents such as verapamil hydrochloride, digitalis, streptokinase, nitroglycerine paparefine, disopyramide phosphate, isosorbide dinitrate, and the like. Anti-ulcer agents such as cimetidine hydrochloride, sopropamide iodide, propantheline bromide, and the like. Bronchodilators such as metaproternal sulfate, aminophylline, albuterol, and the like. Vasodilators such as theophylline, niacin, nicotinate esters, amylnitrate, minoxidil, diazoxide, nifedipine, and the like.

The therapeutic agents which are used in the formulations for the inventive applicator can be well known to the practitioner to which this invention pertains. Classes of therapeutic agents contemplated by the inventive formulations include insecticides, acaricides, parasiticides, growth enhancers, and oil-soluble, nonsteroidal anti-inflammatory drugs (NSAIDs). Specific classes of compounds which fall within these classes include, for example, avermectins, milbemycins, nodulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyridylmethyl derivatives, phenylpyrazoles, and COX-2 inhibitors.

The avermectin and milbemycin series of compounds are potent anthelmintic and antiparasitic agents against a wide range of internal and external parasites. The compounds which belong to this series are either natural products or are semi-synthetic derivatives thereof. The structure of these two series of compounds are closely related and they both share a complex 16-membered macrocyclic lactone ring; however, the milbemycin do not contain the aglycone substitutent in the 13-position of the lactone ring. The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519 to Albers-Schonberg, et al., and the 22,23-dihydro avermectin compounds are disclosed in Chabala, et al., U.S. Pat. No. 4,199,569. For a general discussion of avermectins, which include a discussion of their uses in humans and animals, see “Ivermectin and Abamectin,” W. C. Campbell, e d., Springer-Verlag, New York (1989). Furthermore, bioactive agents such as avermectins or ivermectin can be used in combination with other bioactive agents; and, with respect to a vermectins, ivermectin, and bioactive agent combinations, reference is made to Kitano, U.S. Pat. No. 4,468,390, Beuvry et al., U.S. Pat. No. 5,824,653, von Bittera et al., U.S. Pat. No. 4,283,400, European Patent Application 0 007 812 A1, published June 2, 1980, U.K. Patent Specification 1 390 336, published Apr. 9, 1975, European Patent Application 0 002 916 A2, Ancare New Zealand Patent No. 237 086, Bayer New Zealand Patent 176193, published Nov. 19, 1975, inter alia.

Naturally occurring milbemycins are described in Aoki et al., U.S. Pat. No. 3,950,360 as well as in the various references cited in “The Merck Index” 12^(th) ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, N.J. (1996). Semisynthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Pat. No. 5,077,308, U.S. Pat. No. 4,859,657, U.S. Pat. No. 4,963,582, U.S. Pat. No. 4,855,317, U.S. Pat. No. 4,871,719, U.S. Pat. No. 4,874,749, U.S. Pat. No. 4,427,663, U.S. Pat. No. 4,310,519, U.S. Pat. No. 4,199,569, U.S. Pat. No. 5,055,596, U.S. Pat. No. 4,973,711, U.S. Pat. No. 4,978,677, and U.S. Pat. No. 4,920,148.

Nodulisporic acid and its derivatives are a class of acaricidal, antiparasitic, insecticidal and anthelminitic agents known to a practitioner of the art. These compounds are used to treat or prevent infections in humans and animals. These compounds are described, for example, in U.S. Pat. No. 5,399,582 and WO 96/29073.

Especially preferred therapeutic agents include nodulisporic acid compounds A, B, and C as well as nodulisporic acid derivatives of the formula:

wherein

R₁ is (1) hydrogen,

-   -   (2) optionally substituted alkyl,     -   (3) optionally substituted alkenyl,     -   (4) optionally substituted alkynyl,     -   (5) optionally substituted cycloalkyl,     -   (6) optionally substituted cycloalkenyl,     -   where the substituents on the alkyl, alkenyl, alkynyl,         cycloalkyl and cycloalkenyl are 1 to 3 groups independently         selected from         -   (i) alkyl,         -   (ii) alkyl, where X is O or S(O)_(m).         -   (iii) cycloalkyl,         -   (iv) hydroxy,         -   (v) halogen,         -   (vi) cyano,         -   (vii) carboxy,         -   (viii) NY¹Y², where Y¹ and Y² are     -   independently H or alkyl,         -   (ix) alkanoylamino, and         -   (x) aroylamino wherein said aroyl is optionally substituted             with 1 to 3 groups independently selected from R^(f)     -   (7) aryl or arylalkyl, wherein said aryl is optionally         substituted with 1 to 3 groups independently selected from         R^(f),     -   (8) perfluoroalkyl     -   (9) a 5- or 6-member heterocycle containing from 1 to 4         heteroatoms independently selected from oxygen, sulfur and         nitrogen atoms optionally substituted by 1 to 3 groups         independently selected from hydroxy, oxo, alkyl and halogen, and         which may be saturated or partly unsaturated,

R₂, R₃, and R₄ are independently OR^(a), OCO₂R^(b), OC(O)NR^(c)R^(d); or

R₁ and R₂ represent ═O, ═NOR^(a) or ═N—NR^(c)R^(d);

R₅ and R₆ are H; or

R₅ and R₆ together represent —O—;

R₇ is (1) CHO, or

-   -   (2) the fragment

R₈ is (1) H,

-   -   (2) OR^(a), or     -   (3) NR^(c)R^(d)

R₉ is (1) H, or

-   -   (2) OR^(a);

R₁₀ is (1) CN,

-   -   (2) C(O)OR^(b),     -   (3) C(O)N(OR^(b))R^(c),     -   (4) C(O)NR^(c)R^(d),     -   (5) NHC(O)OR^(b),     -   (6) NHC(O)NRCR^(d),     -   (7) CH₂OR^(a),     -   (8) CH₂OCO₂R^(b),     -   (9) CH₂OC(O)NR^(c)R^(d),     -   (10) C(O)NR^(c)NR^(c)R^(d), or     -   (11) C(O)NR^(c)SO₂R^(b);     -   represents a single or a double bond;

R^(a) is (1) hydrogen,

-   -   (2) optionally substituted alkyl,     -   (3) optionally substituted alkenyl,     -   (4) optionally substituted alkynyl,     -   (5) optionally substituted alkanoyl,     -   (6) optionally substituted alkenoyl,     -   (7) optionally substituted alkynoyl,     -   (8) optionally substituted aroyl,     -   (9) optionally substituted aryl,     -   (10) optionally substituted cycloalkanoyl,     -   (11) optionally substituted cycloalkenoyl,     -   (12) optionally substituted alkylsulfonyl     -   (13) optionally substituted cycloalkyl     -   (14) optionally substituted cycloalkenyl where the substituents         on the alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl,         aroyl, aryl, cycloalkanoyl, cycloalkenoyl, alkylsulfonyl,         cycloalkyl and cycloalkenyl are from 1 to 10 groups         independently selected from hydroxy, alkoxy, cycloalkyl,         arylalkoxy, NR^(g)R^(h), CO₂R_(b), CONR^(c)R^(d) and halogen,     -   (15) perfluoroalkyl,     -   (16) arylsulfonyl optionally substituted with 1 to 3 groups         independently selected from alkyl, perfluoroalkyl, nitro,         halogen and cyano,     -   (17) a 5- or 6-member heterocycle containing 1 to 4 heteroatoms         selected from oxygen, sulfur and nitrogen optionally substituted         by 1 to 4 groups independently selected from alkyl, alkenyl,         perfluoroalkyl, amino, C(O)NR^(c)R^(d), cyano, CO₂R^(b) and         halogen, and which may be saturated or partly unsaturated;

R^(b) is (1) H,

-   -   (2) optionally substituted aryl,     -   (3) optionally substituted alkyl,     -   (4) optionally substituted alkenyl,     -   (5) optionally substituted alkynyl,     -   (6) optionally substituted cycloalkyl,     -   (7) optionally substituted cycloalkenyl, or     -   (8) optionally substituted     -   heterocycle containing from 1 to 4 heteroatoms independently         selected from oxygen, sulfur and nitrogen; where the         substituents on the aryl, alkyl, alkenyl, cycloalkyl,         cycloalkenyl, heterocycle, or alkynyl are from 1 to 10 groups         independently selected from         -   (i) hydroxy,         -   (ii) alkyl,         -   (iii) oxo,         -   (iv) SO₂NR^(g)R^(h),         -   (v) arylalkoxy,         -   (vi) hydroxyalkyl,         -   (vii) alkoxy,         -   (viii) hydroxyalkoxy,         -   (ix) aminoalkoxy,         -   (x) cyano,         -   (xi) mercapto,         -   (xii) alkyl-S(O)_(m),         -   (xiii) cycloalkyl optionally substituted         -   with 1 to 4 groups independently selected from R^(e),         -   (xiv) cycloalkenyl,         -   (xv) halogen,         -   (xvi) alkanoyloxy,         -   (xvii) C(O)NR^(g)R^(h),         -   (xviii) CO₂R^(i),         -   (xix) formyl,         -   (xx) —NR^(g)R^(h),         -   (xxi) 5- to 9-member heterocycle, which may be saturated or             partially unsaturated, containing from 1 to 4 heteroatoms             independently selected from oxygen, sulfur and nitrogen, and             optionally substituted with 1 to 5 groups independently             selected from R^(e),         -   (xxii) optionally substituted aryl, wherein the aryl             substituents are 1,2-methylenedioxy or 1 to 5 groups             independently selected from R^(e),         -   (xxiii) optionally substituted arylalkoxy, wherein the aryl             substituents are 1,2-methylenedioxy or 1 to 5 groups             independently selected from R^(e), and         -   (xxiv) perfluoroalkyl;

R^(c) and R^(d) are independently selected from R^(b); or

R^(c) and R^(d) together with the N to which they are attached form a 3- to 10-member ring containing 0 to 2 additional heteroatoms selected from O, S(O)_(m), and N, optionally substituted with 1 to 3 groups independently selected from R^(g), hydroxy, thioxo and oxo;

R^(e) is (1) halogen,

-   -   (2) alkyl,     -   (3) perfluoroalkyl,     -   (4) —S(O)_(m)R^(i),     -   (5) cyano,     -   (6) nitro,     -   (7) R₁₀(CH₂)v-,     -   (8) R^(i)CO₂(CH₂)v-,     -   (9) R^(i)OCO(CH₂)v-,     -   (10) optionally substituted aryl where the substituents are from         1 to 3 of halogen, alkyl, alkoxy, or hydroxy,     -   (11) SO₂NR^(g)R^(h), or     -   (12) amino;

R^(f) is (1) alkyl,

-   -   (2) X—C₁-C₄ alkyl, where X is O or S(O)_(m),     -   (3) alkenyl,     -   (4) alkynyl,     -   (5) perfluoroalkyl,     -   (6) NY¹Y², where Y¹ and Y² are independently H or alkyl,     -   (7) hydroxy,     -   (8) halogen, and     -   (9) alkanoylamino,

R^(g) and R^(h) are independently

-   -   (1) hydrogen,     -   (2) alkyl optionally substituted with hydroxy, amino, or         CO₂R^(i)     -   (3) aryl optionally substituted with halogen,         1,2-methylenedioxy, alkoxy, alkyl or perfluoroalkyl,     -   (4) arylalkyl, wherein the aryl is optionally substituted with         perfluorolkyl or 1,2-methylenedioxy;     -   (5) alkoxycarbonyl,     -   (6) alkanoyl,     -   (7) alkanoylalkyl,     -   (9) aryl alkoxycarbonyl,     -   (10) aminocarbonyl,     -   (11) monoalkylaminocarbonyl     -   (12) dialkylaminocarbonyl; or

R^(g) and R^(h) together with the N to which they are attached form a 3- to 7-member ring containing 0 to 2 additional heteroatoms selected from O, S(O)_(m), and N, optionally substituted with 1 to 3 groups independently selected from R^(e) and oxo;

R^(i) is (1) hydrogen,

-   -   (2) perfluoroalkyl,     -   (3) alkyl,     -   (4) optionally substituted aryl or arylalkyl, where the aryl         substituents are from 1 to 3 groups independently selected from         halogen, alkyl, alkoxy, and hydroxy;

m is 0 to 2; and

v is 0 to 3; or

a pharmaceutically acceptable salt thereof.

Most especially derivatives include compounds of the formula

wherein R^(x) is selected from the group consisting of: H, CH₃, CH₂CH₃, C(CH₃)₃, CH₂CH₂CH₃, CH₂CH₂OH, CH(CO₂CH₃)OH, CH₂CO₂CH₃, CH₂CH(OCH₂CH₃)₂, CH₂CH₂OCH₂CH₂OH, CH(CH₃)(CH₂)₃C(CH₃)₂OH, (CH₂)₃OH, (CH₂)₄OH, (CH₂)SOH, CH(CH₂OH)CH₂CH₃, NHC(CH₃)₃, CH₂CN, (CH₂)₆OH, CH₂CH(OH)CH₃, CH(CH₂OH)CH₂CH₂CH₃, CH₂CH₂SCH₃, CH₂CH₂SCH₂CH₃, CH₂CONH, CH(CH₃)(CH₂OH)₂, CH₂CH₂NHCH₂CH₂OH, CH(CH₂OH)(CH₂)₃CH₃, CH(CH₂OCH₃)CH₃, (CH₂)₂SH, (CH₂)₄NH₂, CH₂CH₂SO₂CH₃, CH₂CH₂S(O)CH₃, CH(CH(CH₃)₂)CH₂OH, (CH₂)₃NH₂, (CH₂)₃N(CH₂CH₃)₂, (CH₂)₃N(CH₃)₂, OCH₂CH₃, CH₂CH(OH)CH₂OH, OCH₃, CH₂CH₂OCH₃, CH₂CH₂NHC(O)CH₃, C(CH₃)₂CH₂OH, c-C₃H₅, c-C₆H₁₁, (CH₂)₃OCH₂CH₃, CH₂CH≡CH₂, C(CH₂CH₃)(CH₂OH)₂, CH₂C═CH, CH₂CO₂CH₂CH₃, CH₂CH₂F, (CH₂)₃OCH₂)₁₁ CH₃, CH₂CH₂N(CH₃)₂, CH₂CH₂OCH₂CH₂NH₂, CH₂CF₃, NHCH₂CO₂CH₂CH₃, CH(CH₃)CO₂CH₃, C(CH₃)₂CH₂C(O)CH₃, CH(CO₂CH₂CH₃)₂, CH₂CH₃, CH(CH₂CH₂CH₃)CO₂CH₃, CH₂CH₂CH₂OCH₃, C(CH₃)₂C≡CH, (CH₂)₄CH₃, CH(CH₂CH₂CH₃)₂, (CH₂)₅CH₃, CH₂CH₂CO₂H, CH(CH(CH₃)₂)CO₂CH₃, OCH₂CO₂H, CH(CH(CH₃)₂)CH₂OH, CH(CH(CH₃)₂)CH₂OH, CH(CH₃)CH₂OH, CH(CH₃)CH₂OH, CH(CH₃)₂, C(CH₃)₃, (CH₂)CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)OH, (CH₂)₃CH₃, (CH₂)₂OCH₂CH₃, 1 -adamantyl, (CH₂)₈CH₃, CH(CH₃)CH(CH₃)₂, (CH₂)₃NHCH₃, (CH₂)₂N(CH₂CH₃)₂,

An e specially preferred nodulisporamide derivative is one wherein R^(X) is with t-butyl (or “nodulisporamide).

Generally, all classes of such insecticides may be used in this invention. One example of this class include substituted pyridylmethyl derivatives such as imidacloprid. Agents of this class are described, for example, in U.S. Pat. No. 4,742,060 or in EP 892,060.

Pyrazoles such as phenylpyrazoles and N-arylpyrazoles are another class of insecticides which possess excellent insecticidal activity against all insect pests including blood-sucking pests such as ticks, fleas etc., which are parasites on animals. This class of agents kills insects by acting on the gamma-butyric acid receptor of invertebrates. Such agents are described, for example, in U.S. Pat. No. 5,567,429, U.S. Pat. No. 5,122,530, EP 295,117, and EP 846686 A1 (or Banks GB 9625045, filed Nov. 30, 1996 also believed to be equivalent to U.S. Ser. No. 309,229, filed Nov. 17, 1997). It would be well within the skill level of the practitioner to decide which individual compounds can be used in the inventive formulations.

Another advantageous formulation for use with the applicator of the present invention comprises:

an effective amount of at least one compound of the formula:

in which:

-   -   R₁ is a halogen atom, CN or alkyl;     -   R₂ is S(O)_(n)R₃ or 4,5-dicyanoimidazol-2-yl or haloalkyl;     -   R₃ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl or         haloalkyl;     -   R₄ is hydrogen, halogen, NR₅R₆, S(O)_(m)R₇, C(O)R₇, C(O)OR₇,         alkyl, haloalkyl, OR₈ or —N═C(R₉)(R₁₀) substituent;     -   R₅ and R₆ independently represent a hydrogen atom, alkyl,         haloalkyl, C(O)alkyl, S(O)_(r)CF₃ or alkoxycarbonyl or R₅ and R₆         together may combine to form a ring of 5 to 7 members.     -   R₇ represents an alkyl or haloalkyl group;     -   R₈ represents an alkyl, haloalkyl or a hydrogen;     -   R₉ represents an alkyl or a hydrogen;     -   R₁₀ represents an optionally substituted aryl or an optionally         substituted heteroaryl group;     -   R₁₁ and R₁₂ represent, independently of one another, hydrogen,         halogen CN or NO₂;     -   R₁₃ represents a halogen atom or a haloalkyl, haloalkoxy,         S(O)_(q)CF₃ or SF₅ group;     -   m, n, q and r represent, independently of one another, an         integer equal to 0, 1 or 2;     -   X represents a trivalent nitrogen atom or a C—R₁₂, the three         other valencies of the carbon atom forming part of the aromatic         ring;     -   optionally with a pharmaceutically acceptable carrier or         excipient.

Another preferred 1-N-arylpyrazole derivative is a compound wherein the ring formed by the divalent alkylene substituent representing R₅ and R₆ and the nitrogen atom to which R₅ and R₆ are attached has 5, 6 or 7 members or wherein R₁ is CN, R₃ is C₁-C₆-haloalkyl, R₄ is NH₂, R₁₁ and R₁₂ are, independently of one another, hydrogen or halogen and R₁₃ is C₁-C₆-haloalkyl.

Other 1-N-arylpyrazole derivatives to be used in the formulations that may be administered by the inventive device are those of the formula (II)

wherein:

-   -   R₁₀₁ is cyano, —C(O)alkyl, C(S)NH₂, alkyl, haloalkyl, C(═NOH)NH₂         or C(═NNH₂)NH₂;     -   R₁₀₂ is S(O)_(n′)R₁₀₃, alkenyl, haloalkenyl, cycloalkyl,         halocycloalkyl or alkynyl;     -   R₁₀₃ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl or         haloalkynyl;     -   R₁₀₄ is —N═C(R₁₀₅)-Z-R₁₀₆, —N═C(R₁₀₅)—N(R₁₀₇)—R₁₀₈; or         —N(R₁₀₉)—C(R₁₀₅)═NR₁₀₆;     -   R₁₀₅ is hydrogen; alkyl; or alkyl substituted by halogen,         alkoxy, haloalkoxy or —S(O)_(m′)R₁₀₅;     -   R₁₀₆ and R₁₀₇ each independently represent hydrogen, alkyl,         alkenyl or alkynyl, or alkyl substituted by one or more halogen,         alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or     -   S(O)_(m′)R₁₁₅; or alkyl substituted by phenyl or pyridyl each of         which is optionally substituted with one or more groups selected         from halogen, nitro and alkyl group; or     -   R₁₀₇ and R₁₀₈ may form together with the nitrogen to which they         are attached a 3- to 7-membered ring which may additionally         contain one or more heteroatoms selected from oxygen, nitrogen         or sulfur;     -   R₁₀₈ is alkoxy, haloalkoxy, amino, alkylamino, dialkylamino,         —C(O)R₁₁₄ or —S(O)_(t′)R₁₁₀;     -   R₁₀₉, R₁₁₀ and R₁₁₄ are alkyl or haloalkyl;     -   R₁₁₁ and R₁₁₂ are independently selected from halogen, hydrogen,         CN and NO₂     -   R₁₁₃ is selected from halogen, haloalkyl, haloalkoxy,         —S(O)_(q′)CF₃, and —SF₅;     -   R₁₁₅ is alkyl or haloalkyl;     -   X is selected from nitrogen and C—R₁₁₂;     -   Z is O, S(O)_(a′); or NR₁₀₇;     -   a′, m′, n′ and q′ are independently selected from 0, 1, and 2;         and     -   t′ is 0, 1 or 2; and veterinarily acceptable salts thereof.

Another 1-N-arylpyrazole derivatives to be used in topical formulations that may be administered by the present invention are those compounds of formula (III):

wherein:

-   -   R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, alkyl, C(═NOH)NH₂ or         C(═NNH₂)NH₂;     -   R₂₀₂ is S(O)_(h)R₂₀₃, alkenyl, haloalkenyl, cycloalkyl,         halocycloalkyl or alkynyl;     -   R₂₀₃ is alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl or         haloalkynyl;     -   R₂₀₄ is —N(R₂₀₅)C(O)CR₂₀₆R₂₀₇R₂₀₈, —N(R₂₀₅)C(O)aryl, or         —N(R₂₀₅)C(O)OR₂₀₇;     -   R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl,         cycloalkylalkyl, halocycloalkylalkyl, alkoxyalkyl,         haloalkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl;     -   R₂₀₆ is hydrogen, halogen, alkoxy, haloalkoxy, alkoxyalkyl,         haloalkoxyalkyl, formyloxy, alkylcarbonyloxy,         haloalkylcarbonyloxy, alkylthio, haloalkylthio, alkylsulfinyl,         haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino,         dialkylamino, haloalkylamino, di(haloalkyl)amino, cycloalkyloxy,         halocycloalkyloxy, alkoxyalkoxy, haloalkoxyalkoxy,         alkoxyalkoxyalkoxy, aryloxy, or arylalkoxy;     -   R₂₀₇ and R₂₀₈ are independently hydrogen, alkyl, haloalkyl,         cycloalkyl, or halocycloalkyl; or R₂₀₇ and R₂₀₈ may form         together with the carbon to which they are attached a 3- to         7-membered ring which additionally may contain one or more         heteroatoms selected from nitrogen, oxygen and sulfur;     -   X₁ is selected from nitrogen and C—R₂₁₂;     -   R₂₁₁ and R₂₁₂ are independently selected from halogen, hydrogen,         CN and NO₂;     -   R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy,         —S(O)_(k)CF₃, and —SF₅;     -   and     -   h and k are independently selected from 0, 1, and 2;     -   and veterinarily acceptable carrier, excipients and salts         thereof

Another group of 1-N-arylpyrazole derivatives are 4-thiocarbonylpyrazole derivatives of the formula:

in which

-   -   R³⁰¹ is H₂N—C(S)—,     -   R³⁰² is halogenoalkyl, halogenoalkenyl or halogenoalkynyl,     -   R³⁰³ is hydrogen, amino or one of the following groups:         where     -   R³⁰⁴ represents alkyl, halogenoalkyl, alkoxyalkyl or in each         case optionally substituted phenyl or pyridyl,     -   R³⁰⁵ represents hydrogen or alkyl,     -   R³⁰⁶ represents hydrogen, alkyl or in each case optionally         substituted phenyl or pyridyl and     -   R³⁰⁷ represents alkyl, alkenyl, alkinyl, formyl, alkylcarbonyl,         halogenoalkylcarbonyl or alkoxycarbonyl;     -   Ar represents in each case optionally substituted phenyl or         pyridyl and n represents a number 0, 1 or 2.

Additional derivatives of formula (IV) are those wherein

-   -   R³⁰¹ represents H₂N—C(S)—;     -   R³⁰² preferably represents (C₁-C₆)-halogenoalkyl having 1 to 12         halogen atoms; (C₂-C₆)-halogenoalkenyl having 1 to 8 halogen         atoms or (C₁-C₆)-halogenoalkinyl having 1 to 6 halogen atoms;     -   R³⁰³ preferably represents hydrogen, amino or one of the         following groups:         wherein:     -   R³⁰⁴ represents (C₁-C₆)-alkyl, (C₁-C₆)-halogenoalkyl having 1 to         3 halogen atoms, (C₁-C₆)-alkoxy-(C₁-C₆)-alkyl, or represents         phenyl or pyridyl, each of which is optionally monosubstituted         to trisubstituted by identical or different substituents from         the group consisting of cyano, nitro, halogen, C₁-C₆-alkyl,         C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₄-halogenoalkyl, C₁-C₄         halogenoalkoxy or C₁-C₄-halogenoalkylthio having in each case 1         to 5 halogen atoms,     -   R³⁰⁵ represents hydrogen or (C₁-C₆)-alkyl,     -   R³⁰⁶ represents hydrogen, (C₁-C₆)-alkyl, phenyl which is         optionally monosubstituted to trisubstituted by identical or         different substituents from the group consisting of cyano,         nitro, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio,         C₁-C₄-halogenoalkyl, C₁-C₄-halogenoalkoxy or         C₁-C₄-halogenoalkylthio having in each case 1 to 5 halogen atoms         or hydroxyl, or represents pyridyl which is substituted by         cyano, nitro, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy,         C₁-C₆-alkylthio, C₁-C₄-halogenoalkyl, C₁-C₄-halogenoalkoxy or         C₁-C₄-halogenoalkylthio having in each case 1 to 5 halogen         atoms, and     -   R³⁰⁷ represents (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,         formyl, (C₁-C₆)-alkylcarbonyl, (C₁-C₆)-halogenoalkylcarbonyl         having 1 to 6 halogen atoms or (C₁-C₆)-alkoxycarbonyl;     -   Ar preferably represents phenyl or pyridyl, each of which is         optionally monosubstituted to trisubstituted by identical or         different substituents from the group consisting of halogen         halogeno(C₁-C₆)alkyl, halogeno(C₁-C₆)alkylthio,         halogeno(C₁-C₆)alkoxy, (C₁-C₆)alkoxy, methoxy, hydrazine,         (C₁-C₆)-dialkylhydrazino, amino, (C₁-C₆)alkylamino,         di(C₁-C₆)alkylamino, (C₁-C₆)alkylimino, cyano, (C₁-C₆)alkylthio         or the group         in which     -   R³⁰⁸ and R³⁰⁹ are identical or different and represent hydrogen         or (C₁-C₆)-alkyl     -   n¹¹¹ preferably represents a number 0, 1 or 2;     -   R³⁰¹ represents H₂N—C(S)—;     -   R³⁰² particularly preferably represents (C₁-C₄)-halogenoalkyl         having 1 or 9 identical or different halogen atoms from the         group consisting of fluorine, chlorine and bromine,         (C₂-C₄)-halogenoalkenyl having 1 to 5 identical or different         halogen atoms from the group consisting of fluorine, chlorine or         bromine or (C₂-C₄)-halogenoalkynyl having 1 to 5 identical or         different halogen atoms from the group consisting of fluorine,         chlorine and bromine;     -   R³⁰³ especially preferably represents hydrogen, amino or one of         the following groups:         where     -   R³⁰⁴ represents (C₁-C₄)-alkyl, (C₁-C₄)-halogenoalkyl having 1-3         halogen atoms, (C₁-C₄)-alkoxy(C₁-C₂)-alkyl, or phenyl which is         optionally monosubstituted to trisubstituted by identical or         different substituents from the group consisting of hydroxyl,         cyano, nitro, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy,         (C₁-C₂-halogenoalkyl, C₁-C₂-halogenoalkoxy or         C₁-C₂-halogenoalkylthio having in each case 1 to 3 halogen         atoms,     -   R³⁰⁵ represents hydrogen or (C₁-C₄)-alkyl,     -   R³⁰⁶ represents hydrogen, (C₁-C₄)-alkyl or phenyl which is         optionally monosubstituted or disubstituted by identical or         different substituents from the group consisting of hydroxyl,         cyano, nitro, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy,         C₁-C₂-halogenoalkyl, C₁-C₂ halogenoalkoxy or C₁-C₂         halogenoalkylthio having in each case 1 to 3 halogen atoms, in         particular 4-hydroxy-3-methoxy-phenyl, and     -   R³⁰⁷ represents (C₁-C₄)-alkyl, (C₂-C₄)-alkenyl, (C₂-C₄)-alkynyl,         formyl, (C₁-C₄)-alkylcarbonyl, (C₁-C₄,)-halogenoalkylcarbonyl         having 1 to 5 identical or different halogen atoms from the         group consisting of fluorine, chlorine or bromine or         (C₁-C₄)-alkoxycarbonyl;     -   Ar especially preferably represents phenyl or pyridyl, each of         which is optionally monosubstituted to trisubstituted by         identical or different substituents from the group consisting of         fluorine, chlorine, trifluoromethyl, trifluoromethylthio,         trifluoromethoxy, methoxy, hydrazine, dimethylhydrazino, amino,         methylamino, dimethylamino, iminomethyl, cyano, methylthio or         the group         where     -   R³⁰⁸ and R³⁰⁹ are identical or different and represent hydrogen         or (C₁-C₄)-alkyl;     -   n¹¹¹ especially preferably represents a number 0, 1 or 2.

The alkyl groups of the definition of the compounds (1) of the formula (I) generally comprise from 1 to 6 carbon atoms. The ring formed by R₅ and R₆ and the nitrogen atom to which they are attached is generally a 5-, 6- or 7-membered ring.

Unless otherwise specified, alkyl and alkoxy groups are generally lower alkyl and alkoxy groups, that is having from one to six carbon atoms, preferably from one to four carbon atoms. Generally, the haloalkyl, haloalkoxy and alkylamino groups have from one to four carbon atoms. The haloalkyl and haloalkoxy groups can bear one or more halogen atoms; preferred groups of this type include —CF₃ and —OCF₃. Cycloalkyl groups generally have from 3 to 6 carbon atoms, preferably from 3 to 5 carbon atoms, and may be substituted by one or more halogen atoms. Alkenyl, haloalkenyl, alkynyl, and haloalkynyl groups generally contain from 3 to 5 carbon atoms. By the term aryl is generally meant phenyl, pyridyl, furyl, and thiophenyl, each of which is optionally substituted by one or more halogen, alkyl, haloalkyl, nitro, alkoxy, haloalkoxy, hydroxy, amino, alkylamino or dialkylamino. In compounds of formulae (I) to (IV), by the term substituted alkyl is meant alkyl which is substituted by, for example, one or more halogen, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, cyano or —S(O)_(m)R₁₁₅; or alkyl substituted by phenyl or pyridyl each of which is optionally substituted with one or more groups selected from halogen, nitro and alkyl; wherein R₁₁₅ is alkyl or haloalkyl and m is zero, one or two. Preferably in compounds of formula (I), alkyl groups are generally substituted by from one to five halogen atoms, preferably from one to three halogen atoms. Chlorine and fluorine atoms are preferred.

Compounds of formula wherein R₁₀₄ is —N═C(R₁₀₅)-Z-R₁₀₆, Z is NR₁₀₇ and R₁₀₆ represent a hydrogen atom may exist as the tautomeric double bond isomer form —NH—C(R₁₀₅)═N—R₁₀₇. It is to be understood that both such forms are embraced by the present invention.

In compounds of formula (III) the following examples of substituents are provided:

An example of cycloalkylalkyl is cyclopropylmethyl; an example of cycloalkoxy is cyclopropyloxy;

-   -   An example of alkoxyalkyl is CH₃OCH₂—;     -   An example of alkoxyalkoxy is CH₃OCH₂O—;     -   An example of alkoxyalkoxyalkoxy is CH₃OCH₂OCH₂O—;     -   An example of aryloxy is the phenoxy group; and     -   An example of the arylalkoxy group is benzyloxy or         2-phenylethoxy.

Generally, in dialkylamino or di(haloalkyl)amino groups, the alkyl and haloalkyl groups on nitrogen may be chosen independently of one another.

A preferred class of compounds of formula (I) comprises the compounds such that R₁ is CN, R₃ is haloalkyl, R₄ is NH₂, R₁₁ and R₁₂ are, independently of one another, a halogen atom and R₁₃ is haloalkyl. Preferably still, X is C—R₁₂. A compound of formula (I) which is very particularly preferred in the invention is 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole or fipronil.

Compounds of formulae (I)-(III) can be prepared according to one or other of the processes described in Patent Applications WO 87/3781, 93/6089 and 94/21606, and 00/59862 or European Patent Application 295,117 or any other process coming within the competence of a person skilled in the art who is an expert in chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is regarded as having at his disposal, inter alia, the entire contents of “Chemical Abstracts” and of the documents which are cited therein.

In addition to the patent discussing 1-N-arylpyrazoles derivatives discussed previously, one skilled in the art could make these compounds by adopting procedures described in DE 19928155, DE 19853560, WO 2000031043, DE 19650197, WO 9824769, U.S. Pat. No. 6265430, US 2001007876, all of which are herein incorporated by reference.

Insect growth regulating (IGR) compounds are another class of insecticides or acaricides, which are therapeutic agents that may be administered by the inventive applicator. Compounds belonging to this group are well known to the practitioner and represent a wide range of different chemical classes. These compounds all act by interfering with the development or growth of the insect pests. Compounds with an ovicidal and/or larvicidal effect on the immature stages of various ectoparasites are already known, for example from U.S. Pat. No. 5,439,924. Among these compounds described are those IGR compounds, which act either by blocking the development of the immature stages (eggs and larvae) into adult stages, or by inhibiting the synthesis of chitin. Insect growth regulators are described, for example, in U.S. Pat. No. 3,748,356; U.S. Pat. No. 3,818,047; U.S. Pat. No. 4,225,598; U.S. Pat. No. 4,798,837; and U.S. Pat. No. 4,751,225, as well as in EP 179,022 or U.K. 2,140,010. French Patent No. A-2,713,889 generally describes an IGR combination comprising at least one compound with juvenile hormone activity and chitin synthesis inhibitors, with at least one of three N-arylpyrazole compounds, in particular fipronil or thiofipronil, to control many harmful insects belonging to very varied orders.

Examples of IGR compounds which may be used in this invention include compounds which mimic juvenile hormones, in particular:

-   -   azadirchtin-Agridyne     -   diofenolan (Ciba Geigy now Novartis)     -   fenoxycarb (Ciba Geigy now Novartis)     -   hydroprene (Sandoz now Novartis)     -   kinoprene (Sandoz now Novartis)     -   methoprene (Sandoz now Novartis)     -   pyriproxyfen (Sumitomo/Mgk)     -   tetrahydroazadirachtin (Agridyne)     -   4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridizin-3(2H)-one     -   and chitin-synthesis inhibitors, in particular:     -   chlorfluazuron (Ishihara Sangyo)     -   cyromazine (Ciba Geigy now Novartis)     -   diflubenzuron (Solvay Duphar)     -   fluazuron (Ciba Geigy now Novartis)     -   flucycloxuron (Solvay Duphar)     -   flufenoxuron (Cyanamid)     -   hexaflumuron (Dow Elanco)     -   lufenuron (Ciba Geigy now Novartis)     -   tebufenozide (Rohm & Haas)     -   teflubenzuron (Cyanamid)     -   triflumuron (Bayer).

These compounds are defined by their international common name (The Pesticide Manual, 10^(th) edition, 1994, Ed. Clive Tomlin, Great Britain).

Chitin-synthesis inhibitors also include compounds such as 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-((trifluoromethyl))phenylurea, 1 -(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy))phenylurea and 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoro-methyl)phenylurea. Novaluron (Isagro, Italian company) is also an example of an IGR compound.

Preferred IGR compounds include methoprenes, pyriproxyfens, hydroprene, cyromazine, lufenuron, 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea and novaluron.

Estrogens, progestins, and androgens refers to classes of chemical compounds which are also well known to a practitioner in this art. In fact, estrogens and progestins are among the most widely prescribed drugs and are used, for example, alone or in combination for contraception or hormone replacement therapy in post menopausal women. Estrogens and progestins occur naturally or are prepared synthetically. This class of compounds also includes estrogens or progesterone receptor antagonists. Antiestrogens, such as tamoxifen and clomiphene, are used to treat breast cancer and infertility. Antiprogestives are used as contraceptives and anticancer drugs, as well as to induce labor or terminate a pregnancy.

The androgens and antiandrogens structurally related to the estrogens and progestins as they are also biosynthesized from cholesterol. These compounds are based on testosterone. Androgens are used for hypogonadism and promote muscle development. Antiandrogens are used, for example, in the management of hyperplasia and carcinoma of the prostate, acne, and male pattern baldness as well as in the inhibition of the sex drive in men who are sex offenders. Estrogen, progestins, and androgens are described, for example, in “Goodman & Gilman's The Pharmacological Basis of Therapeutics,” 9^(th) ed., J. G. Handman and L. Elimbird, eds., Ch. 57 to 60, pp. 1411-1485, McGraw Hill, New York (1996) or in “Principles of Medicinal Chemistry,” 2^(nd) ed., W. O. Foye, ed., Ch. 21, pp. 495-559, Lea & Febiger, Philadelphia (1981).

Estrogens, progestins and androgens are also used in animal husbandry as growth promoters for food animals. It is known in the art that compounds of these classes act as growth-promoting steroids in animals such as cattle, sheep, pigs, fowl, rabbits, etc. Delivery systems to promote the growth of animals are described, for example, in U.S. Pat. No. 5,401,507, U.S. Pat. No. 5,288,469, U.S. Pat. No. 4,758,435, U.S. Pat. No. 4,686,092, U.S. Pat. No. 5,072,716 and U.S. Pat. No. 5,419,910.

NSAIDs are well known in the art. The classes of compounds which belong to this group include salicylic acid derivatives, para-aminophenol derivatives, indole and indene acetic acids, heteroaryl acetic acids, arylpropionic acids, anthranilic acids (fenamates), enolic acids, and alkanones. NSAIDs exert their activity by interfering with prostaglandin biosynthesis by irreversibly or reversibly inhibiting cycloxygenase. Also included are COX-2 inhibitors which act by inhibiting the COX-2 receptor. Compounds of this group possess analgesic, antipyretic and nonsteroidal anti-inflammatory properties. Compounds belonging to these classes are described, for example, in Chapter 27 of Goodman and Gilman on pages 617 to 658 or in Ch. 22 of Foye on pages 561 to 590 as well as in U.S. Pat. No. 3,896,145; U.S. Pat. No. 3,337,570; U.S. Pat. No. 3,904,682; U.S. Pat. No. 4,009,197; U.S. Pat. No. 4,223,299; and U.S. Pat. No. 2,562,830, as well as the specific agents listed in The Merck Index. Especially preferred COX-2 inhibitors include 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one or 3-(cyclopropylethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one, including the polymorphic B form of this compound, and the pharmaceutically acceptable salts or hydrates of these compounds. Polymorphic B Form of 3-(cyclopropylmethoxy)-4-[4-(methylsulfonyl)phenyl]-5,5-dimethyl-5H-furan-2-one is characterized by the following parameters cristalline system Trigonal space group R-3 Description hexagonal unit-cell dimensions a (Å) 18.183 b (Å) 18.183 c (Å) 26.950 α (°) 90 β (°) 90 γ (°) 120 unit-cell volume (Å³) 7716.5 number of molecules per unit-cell Z 18 Temperature of measurement (° K) 293 calculated specific gravity 1.303 weight absorption coefficient (cm⁻¹) 2.11

and further characterized by the following X-ray diffraction data calculated from crystalline structure: d(Angs) Intensity 13,596 w 10,238 w 9,092 s 8,983 m 7,558 vw 6,798 vw 6,39 m 6,39 vw 6,194 vw 5,812 m 5,812 w 5,444 w 5,444 vw 5,249 s 5,119 s 5,1 vw 4,546 vw 4,532 s 4,532 s 4,492 m 4,461 m 4,448 w 4,311 vw 4,311 vw 4,155 s 4,155 m 4,056 vw 4,056 vw 4,027 vw 4,027 vw 3,995 m 3,995 w 3,895 w 3,74 vw 3,665 vw 3,665 vw 3,581 m 3,489 vw 3,489 vw 3,459 vw 3,436 vw 3,436 vw 3,413 w 3,413 vw 3,399 vw 3,393 m 3,393 vw 3,233 vw 3,209 w 3,209 vw 3,195 w 3,195 vw 3,184 m 3,184 vw 3,179 vw 3,128 vw 3,067 vw 3,031 vw 3,001 vw 3,001 vw 2,994 vw 2,958 vw 2,958 vw 2,932 vw 2,906 vw 2,906 vw 2,888 vw 2,853 vw 2,844 vw 2,813 vw 2,768 vw 2,753 vw 2,729 vw 2,729 vw 2,722 vw 2,722 vw 2,719 vw 2,667 w 2,667 vw 2,634 vw 2,624 vw 2,608 vw 2,522 vw 2,519 vw 2,519 vw 2,512 vw 2,504 vw 2,504 vw 2,501 vw 2,464 vw 2,464 vw 2,455 vw 2,438 vw 2,428 vw 2,428 vw 2,417 vw 2,364 vw 2,339 vw 2,301 vw

Macrolides are a class of antibiotics which contain a many-membered lactone ring to which are attached one or more deoxy sugars. Macrolides are generally bacteriostatic, but have been shown to be bacteriocidal in high concentration against very susceptible organisms. Macrolides are most effective against gram-position cocci and bacilli, although they do possess some activity against some gram-negative organism. Macrolides exert their bacteriostatic activity by inhibiting bacterial protein synthesis by binding reversibly to the 50 S ribosomal subunit. (“Goodman & Gillman's the Pharmacological Basis of Therapeutics,” 9th ed., J. G. Hadman & L. E. Limbird, eds., ch. 47, pp. 1135-1140, McGraw-Hill, New York (1996)).

The macrolides as a class are colorless and usually crystalline. The compounds are generally stable in near neutral solution, but they only have limited stability in acid or base solutions. The reason for this is because the glycosidic bonds hydrolyze in acid and the lactone ring saponifies in base (“Principles of Medicinal Chemistry,” 2nd ed., W. F. Foye, ed., ch. 31, pp. 782-785, Lea & Febiger, Philadelphia (1981)).

The macrolide anthelmintic compounds contemplated for use in the present invention are also well known to a practitioner of this art. These compounds include avermectins and milbemycins discussed above. Non-limiting examples of compounds belonging to this class are represented by the following structure:

where the broken line indicates a single or a double bond at the 22,23-positions;

-   -   R₁ is hydrogen or hydroxy provided that R₁ is present only when         the broken line indicates a single bond;     -   R₂ is alkyl of from 1 to 6 carbon atoms or alkenyl of from 3 to         6 carbon atoms or cycloalkyl of from 3 to 8 carbon atoms;     -   R₃ is hydroxy, methoxy or ═NOR₅ where R₅ is hydrogen or lower         alkyl; and     -   R₄ is hydrogen, hydroxy or         where R₆ is hydroxy, amino, mono-or di-lower alkylamino or lower         alkanoylamino.

Additional compounds are avermectin Bla/Blb (abamectin), 22,23-dihydro avermectin Bla/Blb (ivermectin) and the 4″-acetylamino-5-ketoximino derivative of avermectin Bla/Blb. Both abamectin and ivermectin are approved as broad-spectrum antiparasitic agents. The 4″-acetyl amino-5-ketoximino derivatives of avermectin Bla/Blb has the following structural formula:

where R₂ is isopropyl or sec-butyl.

The avermectin products are generally prepared as a mixture of at least 80% of the compound where R₂ is sec-butyl and no more than 20% of the compound where R₂ is isopropyl. Other known avermectins include ememectin, eprinomectin and doramectin. Preferred milbemycin compounds which may be used as therapeutic agents include milbemycin α_(i) and moxidectin.

The monosaccharide avermectin derivatives are also useful in combination with the present invention, especially where an oxime substitution is present on the 5-position of the lactone ring. Such compounds are described, for example, in EP 667,054. Also contemplated are all pharmaceutical and veterinary acceptable acid or base salt forms of these compounds as well as the corresponding ester and amide derivatives of these compounds, where applicable. Specific compounds which belong to this class of macrolide antiparasitic agents are well known to the practitioner of this art.

The bioactive agent in the present invention can be a macrolide, as macrolides are soluble in many organic solvents but are only slightly water soluble.

Macrolides as a class include the erythromycin and its derivatives as well as other derivatives such as the azalides. Erythromycin (MW 733.94 daltons) is the common name for a macrolide antibiotic produced by the growth of a strain of Streptomyces erythreous. It is a mixture of three erythromycins, A, B and C consisting largely of erythromycin A. Its chemical name is (3R*,4S*,5S*,6R*,7R*,9R*, 11R*,12R* ,13S*,14R*)-4-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)-oxy]-14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-6[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexapyranosyl]oxy]oxacyclotetradecane-2,10-dione, (C₃₇H₆₇NO₁₃).

Erythromycin has a broad and essentially bacteriostatic action against many Gram-positive and some Gram-negative bacteria as well as other organisms including mycoplasmas, spirochetes, chlamydiae and rickettsiae. In humans, it finds usefulness in the treatment of a wide variety of infections. It finds wide application in veterinary practice in the treatment of infectious diseases such as pneumonias, mastitis, metritis, rhinitis, and bronchitis in cattle, swine and sheep.

Other derivatives of erythromycins include carbomycin, clarithromycin, josamycin, leucomycins, midecamycins, mikamycin, miokamycin, oleandomycin, pristinamycin, rokitamycin, rosaramicin, roxithromycin, spiramycin, tylosin, troleandomycin, and virginiamycin. As with the erythromycins, many of these derivatives exist as component mixtures. For example, carbomycin is a mixture of carbomycin A and carbomycin B. Leucomycin exists as a mixture of components A₁, A₂, A₃, A₉, B₁-B₄, U and V in various proportions. Component A₃ is also known as josamycin and leucomycin V is also known as miokomycin. The major components of the midecamycins is midecamycin A and the minor components are midecamycins A₂, A₃ and A₄. Likewise, mikamycin is a mixture of several components, mikamycin A and B. Mikamycin A is also known as virginiamycin M₁. Pristinamycin is composed of pristinamycins I_(A), I_(B), and I_(C), which are identical to virginiamycins B₂, B₁₃ and B₂ respectively, and pristinamycin II_(A) and II_(B), which are identical to virginiamycin M₁ and 26,27-dihydrovirginiamycin M₁. Spiramycin consists of three components, spiromycin I, II, and III. Virginiamycin is composed of virginiamycin S₁ and virginiamycin M₁. All these components may be used in this invention. Sources of these macrolides are well known to the practitioner and are described in the literature in references such as “The Merck Index,” 12th ed., S. Budarari, ed., Merck & Co., Inc., Whitehouse Station, N.J. (1996).

The azalides are semisynthetic macrolide antibiotics related to erythromycin A and exhibit similar solubility characteristics. The structure of azithromycin is known. Useful azalide compounds are disclosed in EP 508699, herein incorporated by reference. The corresponding basic and acid addition salts and ester derivatives of the macrolides compounds are also contemplated for use in this invention. These salts are formed from the corresponding organic or inorganic acids or bases. These derivatives include the customary hydrochloride and phosphate salts as well as the acetate, propionate and butyrate esters. These derivatives may have different names. For example, the phosphate salt of oleandomycin is matromycin and the triacetyl derivative is troleandomycin. Rokitamycin is leucomycin V 4-B-butanoate, 3B-propionate.

Combinations of one or more of the therapeutic agents described above are contemplated. For example the therapeutic agents nodulisporamide derivatives or 1-N-arylpyrazoles may be combined with other insecticides, parasiticides, and acaricides. Such combinations include anthelminitic agents, such as those discussed above which include ivermectin, avermectin, and emamectin, as well as other agents such as thiabendazole, praziquantel, febantel or morantel. Alternatively, other combinations may include imidicloprid or a COX-2 inhibitor.

Non-limiting examples of topical formulations that are preferred include those comprising:

-   -   a) a pharmaceutically active combination consisting of at least         one macrocyclic lactone and at least one compound selected from         the group consisting of praziquantel, morantel and pyrantel;     -   b) optionally, a thickening agent;     -   c) a non-aqueous solvent; and     -   d) optionally, an antioxidant, a colorant, an acidifying         stabilizer, an opacifier, a preservative and a crystallization         inhibitor, wherein the pharmaceutically active combination is         disclosed in the non-aqueous solvent.         These formulations may be of the spot-on or pour-on type.

Other preferred spot-on and pour-on compositions include formulations comprising:

(A) 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole; or

(B) 1-N-phenylpyrazole derivative of the formula:

Other preferred spot-on or pour-on formulations are those comprising, for example, comprising from 0.05 to 25% weight/volume, relative to the total solution, of a compound of the formula:

wherein:

-   -   R¹ represents H₂N—CS—;     -   R² represents S(O)_(n)R, 4,5-dicyanoimidazol-2-yl or haloalkyl;     -   R³ represents alkyl, haloalkyl, haloalkenyl or haloalkynyl;     -   R⁴ represents hydrogen, halogen, alkyl, haloalkyl, amino or a         compound selected from the group consisting of         wherein     -   R⁵ represents alkyl, halogenoalkyl, alkoxyalkyl or in each case         unsubstituted or substituted phenyl or pyridyl,     -   R₆ represents hydrogen or alkyl,     -   R⁷ represents hydrogen, alkyl or in each case unsubstituted or         substituted phenyl or pyridyl,     -   R⁸ represents alkyl, alkenyl, alkynyl, formyl, alkylcarbonyl,         halogenoalkylcarbonyl, or alkoxycarbonyl,     -   or a radical NR⁹R⁹R¹⁰, S(O)_(m)R¹¹, C(O)R¹¹, C(O)R¹¹, OR¹², or         —N═C(R¹³)(R¹⁴)     -   wherein     -   R⁹ and R¹⁰ independently represent a hydrogen atom or an alkyl,         haloalkyl, C(O)alkyl, alkyoxycarbonyl or a S(O)_(r)CF₃ radical;         or R⁹ and R¹⁰ may together form a divalent alkenyl radical which         may be interrupted by one or two heteroatoms;     -   R¹¹ represent an alkyl or haloalkyl radical;     -   R¹² represents an alkyl or haloalkyl radical or a hydrogen atom;     -   R¹³ represents an alkyl radical or a hydrogen atom;     -   R¹⁴ represents a phenyl or a heteroaryl group optionally         substituted with one or more halogen atoms or OH, —O-alkyl,         S-alkyl, cyano or alkyl;     -   m, n q, r represents independently of each other an integer         equal to 0, 1, or 2;     -   Ar represents unsubstituted or substituted phenyl or pyridyl,         and n represents a number 0, 1 or 2,         wherein the composition comprises from 0.05 to 25% weight/volume         of the compound of formula (II), and the compound of         formula (II) is applied in a dose between 0.1 and 2 mg/kg animal         weight.

Especially, preferred are those, for example, which contain Frontline®, Frontline plus®, or Revolution®, as described in U.S. Pat. Nos. 6,426,333; 6,482,425; 6,395,765; 6,096,329; and 6,685,954.

Other especially preferred spot-on or pour-on formulations include: synergistic spot-on compositions for the long lasting protection against ectoparasites on mammals which comprises synergistic amounts

-   -   (A) at least one compound of the formula:         in which:     -   R₁ is CN or methyl or a halogen atom;     -   R₂ is S(O)_(n)R₃ or 4,5-dicyanoimidazol-2-yl or haloalkyl;     -   R₃ is alkyl or haloalkyl;     -   R₄ represents a hydrogen or halogen atom; or a radical NR₅ R₆,         S(O)_(m)R₇, C(O)R₇, C(O)O—R₇, alkyl, haloalkyl, or OR₈ or a         radical —N═C(R₉)(R₁₀);     -   R₅ and R₆ independently represent a hydrogen atom or an alkyl,         haloalkyl, C(O)alkyl, alkoxycarbonyl or S(O)_(r)—CF₃ radical; R₅         and R₆ may together form a divalent alkylene radical which may         be interrupted by one or two divalent hereto atoms or;     -   R₇ represents an alkyl or haloalkyl radical;     -   R₈ represents an alkyl or haloalkyl radical or a hydrogen atom;     -   R₉ represents an alkyl radical or a hydrogen atom;     -   R₁₀ represents a phenyl or heteroaryl group optionally         substituted with one or more halogen atoms or one or more         substituents selected from the group consisting of OH, —O-alkyl,         S-alkyl, cyano or alkyl;     -   R₁₁ and R₁₂ represent, independently of each other, hydrogen,         halogen, CN or NO₂;     -   R₁₃ represents a halogen atom or a haloalkyl, haloalkoxy,         S(O)_(q)CF₃ or SF₅ group;     -   m, n, q and r represent, independently of each other, an integer         equal to 0, 1 or 2;     -   X represents a trivalent nitrogen atom or a radical C—R₁₂, the         other three valency positions of the carbon atom forming part of         the aromatic ring;     -   with the proviso that when R₁ is methyl, then R₃ is haloalkyl,         R₄ is NH₂, R₁₁ is Cl, R₁₃ is CF₃ and X is N; or R₂ is         4,5-dicyanoimidazol-2-yl, R₄ is Cl, R₁₁, is Cl, R₁₃ is CF₃ and X         is ═C—Cl;

(B) at least one insect growth regulator (IGR) that mimics juvinile hormones;

(C) imidacloprid; and

a fluid vehicle comprising at least one customary spot-on formulation adjuvant; or a composition comprising

(A) an effective amount of at least one compound of the formula

in which:

-   -   R₁ is a halogen atom, CN or methyl;

R₂ is S(O)_(n)R₃ or 4,5-dicyanoimidazol-2-yl or haloalkyl;

-   -   R₃ is alkyl or haloalkyl;     -   R₄ represents a hydrogen or halogen atom or an NR₅R₆,         (S)O)_(m)R₇, C(O)R₇, alkyl, haloalkyl or O₈ radical or an         —N═C(R₉)(R₁₀) radical;     -   R₅ and R₆ independently represent a hydrogen atom or an alkyl,         haloalkyl, C(O)alkyl, S(O)_(r)CF₃ or alkoxycarbonyl radical or         R₅ and R₆ can together form a divalent alkylene radical which is         optionally interrupted by one or two divalent heteroatoms;     -   R₇ represents an alkyl or a haloalkyl radical;     -   R₈ represents an alkyl or haloalkyl radical or a hydrogen atom;     -   R₉ represents an alkyl radical or a hydrogen atom;     -   R₁₀ represents an optionally substituted aryl or an optionally         substituted heteroaryl group;     -   R₁₁ and R₁₂ represent, independently of one another, hydrogen ,         halogen CN or NO₂;     -   R₁₃ represents a halogen atom or a haloalkyl, haloalkoxy,         S(O)_(q)CF₃ or SF₅ group;     -   m, n, q and r represent, independently of one another, an         integer equal to 0, 1 or 2;     -   X represents a trivalent nitrogen atom or a C—R₁₂ radical, the         three other valencies of the carbon atom forming part of the         aromatic ring;     -   with the proviso that, when R₁ is mehyl, then R₃ is haloalkyl,         R₄ is Cl, R₁₃ is CF₃ and X is N or else R₂ is         4,5-dicyanoimidazol-2-yl, R₄ is Cl, R₁₁ is Cl, R₁₃ is CF₃ and X         is C—Cl; and/or

(B) a pharmaceutical or veterinary effective amount of a macrocyclic lactone antihelmintic or antiparasitic agent;

(2) a pharmaceutically or veterinary acceptable liquid carrier vehicle; and

(3) optionally, a crystallization inhibitor,

with spot-on compositions comprising

(A) 1-[2,6-Cl₂-4-CF₃ phenyl]-3-CN-4-[SO—CF₃]-5-NH₂ pyrazole; and

(B) ivermectin and milbemectin; or

where the composition comprises

(A) 1-[2,6-Cl₂-4-CF₃ phenyl]-3-CN-4-[SO—CF₃]-5-NH₂pyrazole; and

(B) selamectin,

being especially p referred. Other preferred macrocyclic lactones include a vermectins, abamectin, doramectin, moxidectin, and milbemycin.

Frontline® is a spot-on product comprises fipronil, ethanol, polvidone, Tween 80, butylhydroxytoluene, butlyhydroxyanisole and diethylene glycol monomethylether. Frontline Plus® contains the same ingredients as Frontline® except that it further includes (S)-methoprene. Revolution® is a spot-on product comprising selamectin in isopropanol, polyvidone, Tween 80, butylhydroxytoluene, dipropylene glycol monomethylether.

The topical formulations used in the present invention may include other formulations adjuvants well know to a practitioner in this art. Non-limiting examples of these additives are as follows:

The thickeners are well known to a practitioner of this art and may be added to these formulations. Compounds which function as thickeners include, for example, povidone, maltodextrin, polydextrate, EMDEX (dextrates), carboxypolymethylene (Carbomer®), polyethylene glycol and celluloses, such as hydroxypropyl celluloses. An especially preferred thickener is povidone. Thickeners may be present in amounts of from about 0.1% to about 25%.

Opacifiers may be added to absorb and/or reflect certain light and/or energy of certain wavelengths and may thus enhance the stability of the formulations. Opacifiers include, for example, zinc oxide or titanium dioxide and may be present in amounts from about 0.5 to 2.5%. Titanium dioxide is especially preferred. These compounds are well known to practitioners of this art.

Additionally, the formulations may contain other inert ingredients such as antioxidants, preservatives, or pH stabilizers. These compounds are well known in the formulation art. Antioxidant such as an alpha tocopheral, ascorbic acid, ascrobyl palmitate, fumeric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), monothioglycerol and the like, may be added to the present formulation. The antioxidants are generally added to the formulation in amounts of from about 0.01 to about 2.0%, based upon total weight of the formulation, with about 0.05 to about 1.0% being especially preferred. Preservatives, such as the parabens (methylparaben and/or propylparaben), are suitably used in the formulation in amounts ranging from about 0.01 to about 2.0%, with about 0.05 to about 1.0% being especially preferred. Other preservatives include benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, and the like. Preferred ranges for these compounds include from about 0.01 to about 5%.

Colorants may be added to the formulations. Specific colorants include, for example, dyes, an aluminum lake, caramel, colorant based upon iron oxide or a mixture of any of the foregoing. Especially useful are organic dyes and titanium dioxide. Preferred ranges include from about 0.1% to about 25%.

Solvents for the formulations would be readily known in the art and include, for example, glycerol formal, 1-methylpyrrolidone (NMP), propylene, glycol, polyethylene glycol, benzyl alcohol, mixtures of glyceride/triglyceride and their derivatives, such as caprilic/capric acid triglyceride, or fatty acid esters (miglyol products) diethylene glycol monoethyl ether (transcutol®), lauroglycol 90, dimethylfomamide (DMF), dimethyl sulfoxide (DMSO) and mixtures of these solvents.

Administration of the inventive formulation may be intermittent in time and may be administered daily, weekly, biweekly, monthly, bimonthly, quarterly, or even for longer durations of time. The time period between treatments depends upon factors such as the parasite(s) being treated, the degree of infestation, the type of mammal or bird and the environment where it resides. It is well within the skill level of the practitioner to determine a specific administration period for a particular situation.

Spot-on and pour-on formulations may be prepared by dissolving the therapeutic agents into the pharmaceutically or veterinary acceptable vehicle. Alternatively, the spot-on formulation can be prepared by encapsulation of the active ingredient to leave a residue of the therapeutic agent on the surface of the animal. These formulations will vary with regard to the weight of the therapeutic agent in the combination depending on the therapeutic agent, the species of host animal to be treated, the severity and type of infection and the body weight of the host. The compounds may be administered continuously, particularly for prophylaxis, by known methods. Generally, a dose of from about 0.001 to about 10 mg per kg of body weight given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but, of course, there can be instance where higher or lower dosage ranges are indicated and such are within the scope of this invention. It is well within the routine skill of the practitioner to determine a particular dosing regimen for a specific therapeutic agent for a specific host and parasite.

Preferably, a single formulation containing for example, a 1-N-arylpyrazole derivative in a substantially liquid carrier and in a form which makes possible a single application, or an application repeated a small number of times, will be administered to the animal over a highly localized region of the animal, preferably between the two shoulders. Most preferably, this localized region has a surface area of less than 10 cm, especially between 5 and 10 cm² area.

It also may be preferable to use controlled-release formulations.

It is understood that the dosage values which are thus indicated are average values which may vary within a wide range. For example, a formulation having defined doses of 1-N-arylpyrazole-type derivative and of an IGR compound will be administered to animals having relatively different weights. Consequently, the doses actually applied are often smaller or larger by a factor which may be up to 2, 3 or 4 relative to the preferred dose, without entailing any toxic risk for the animal in the case of an overdose, and while at the same time retaining real efficacy, possibly of shorter duration, in the case of an underdose.

The spot-on formulations that are used in present invention provide for the topical administration of a concentrated solution, suspension, microemulsion or emulsion for intermittent application to a spot on the animal, generally between the two shoulders (solution of spot-on type). It has been discovered that the inventive formulations are especially active against parasites when the formulations are applied to mammals and birds, especially poultry, dogs, cats, sheep, pigs, cattle zebras, horses, donkeys, mice, chipmunks and tree squirrels.

Also contemplated are the pharmaceutically or veterinary-acceptable acid or base salts, where applicable, of the therapeutic agents provided for herein. The term “acid” contemplates all pharmaceutically or veterinary acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuric acids, phosphoric acids and nitric acids. Organic acids include all pharmaceutically or veterinary-acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. Preferred acids are straight chain or branched, saturated or unsaturated C₁-C₂₀ aliphatic carboxylic acids, which are optionally substituted by halogen or by hydroxyl groups, or C₆-C₁₂ aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, α-hydroxy acids, such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tataric acid and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically or veterinary-acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid and lactobionic acid.

The term “base” contemplates all pharmaceutically or veterinary acceptable inorganic or organic bases. Such bases include, for example, the alkali metal and alkaline earth metal salts, such as the lithium, sodium, potassium, magnesium or calcium salts. Organic bases include the common hydrocarbyl and heterocyclic amine salts, which include, for example, the morpholine and piperidine salts.

The organic solvent for the liquid carrier vehicle will preferably have a dielectric constant of between about 10 and about 35, preferably between about 20 and about 30, the content of this solvent in the overall composition preferably representing the remainder of 100% of the composition. It is well within the skill level of the practitioner to select a suitable solvent on the basis of these parameters.

The organic cosolvent for the liquid carrier vehicle will preferably have a boiling point of less than about 100° C., preferably of less than about 80° C., and will have a dielectric constant of between about 10 and about 40, preferably between about 20 and about 30; this cosolvent can advantageously be present in the composition according to a weight/weight (W/W) ratio with respect to the solvent of between about 1/15 and about 1/2; the cosolvent is volatile in order to act in particular as drying promoter and is miscible with water and/or with the solvent. Again, it is well within the skill level of the practitioner to select a suitable solvent on the basis of these parameters.

The organic solvent for the liquid carrier includes the commonly acceptable organic solvents known in the formulation art. These solvents may be found, for example, in Remington Pharmaceutical Science, 16^(th) Edition (1986). These solvents include, for example, acetone, ethyl acetate, methanol, ethanol, isopropanol, dimethylformamide, dichloromethane or diethylene glycol monoethyl ether (Transcutol). These solvents can be supplemented by various excipients according to the nature of the desired phases, such as C₈-C10 caprylic/capric triglyceride a hydrogenated or fractionated coconut oil (Estasan or Miglyol 812), oleic acid or propylene glycol.

The liquid carrier may also comprise a microemulsion. Microemulsions are also well suited as the liquid carrier vehicle. Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids.

Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.

The oily phase can in particular be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds. The oily phase preferably comprises triglycerides and more preferably medium-chain triglycerides, for example C₈-C₁₀ caprylic/capric triglyceride. The oily phase will represent, in particular, from about 2 to about 15% more, particularly from about 7 to about 10%, preferably from about 8 to about 9%, V/V of the microemulsion. Suitable oils for the oily phase are known in the art and are described, for example, in U.S. Pat. No. 6,036,394; U.S. Pat. No. 5,580,574; U.S. Pat. No. 6,174,540 and WO 97/37653, herein incorporated by reference.

The aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. Propylene glycol, diethylene glycol monoethyl ether and dipropylene glycol monoethyl ether are especially preferred. Generally, the aqueous phase will represent a proportion from about 1 to about 4% V/V in the microemulsion.

Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolysed C₈-C₁₀ glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, the cosurfactants include short-chain alcohols, such as ethanol and propanol.

Some compounds are common to the three components discussed above, i.e., aqueous phase, surfactant and cosurfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation.

The cosurfactant to surfactant ratio will preferably be from about 1/7 to about 1/2. There will preferably be from about 25 to about 75% V/V of surfactant and from about 10 to about 55% V/V of cosurfactant in the microemulsion.

Likewise, the co-solvents are also well known to a practitioner in the formulation art. Preferred co-solvents are those which are promoters of drying and include, for example, absolute ethanol, isopropanol (2-propanol) or methanol.

The crystallization inhibitor can in particular be present in a proportion of about 1 to about 20% (W/V), preferably of about 5 to about 15%. The inhibitor preferably corresponds to the test in which 0.3 ml of a solution comprising 10% (W/V) of the compound of formula (I) in the liquid carrier and 10% of the inhibitor are deposited on a glass slide at 20° C. and allowed to stand for 24 hours. The slide is then observed with the naked eye. Acceptable inhibitors are those whose addition provides for few or no crystals, and in particular less than 10 crystals, preferably 0 crystals.

Optionally, the formulation can optionally comprise water, in particular in a proportion of 0 to about 30% (volume by volume V/V), in particular of 0 to about 5%, although this is not always preferred.

The formulation can also comprise an antioxidizing agent intended to inhibit oxidation in air, this agent being particularly present in a proportion of about 0.005 to about 1% (W/V), preferably of about 0.01 to about 0.05%.

Crystallization inhibitors which may be included in the spot-on or pour-on formulation. Non-limiting examples of crystallization inhibitors include:

-   -   polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl         acetate and of vinylpyrrolidone, polyethylene glycols, benzyl         alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated         esters of sorbitan; lecithin or sodium carboxymethylcellulose;         or acrylic derivatives, such as methacrylates and others,     -   anionic surfactants, such as alkaline stearates, in particular         sodium, potassium or ammonium stearate; calcium stearate or         triethanolamine stearate; sodium abietate; alkyl sulphates, in         particular sodium lauryl sulphate and sodium cetyl sulphate;         sodium dodecylbenzenesulphonate or sodium dioctyl         sulphosuccinate; or fatty acids, in particular those derived         from coconut oil,     -   cationic surfactants, such as water-soluble quaternary ammonium         salts of formula N⁺R^(′)R^(″)R^(′″)R^(″″)Y⁻, in which the R         radicals are identical or different optionally hydroxylated         hydrocarbon radicals and Y⁻ is an anion of a strong acid, such         as halide, sulphate and sulphonate anions;         cetyltrimethylammonium bromide is one of the cationic         surfactants which can be used,     -   amine salts of formula N⁺R⁴⁰ R^(″)R^(′″), in which the R         radicals are identical or different optionally hydroxylated         hydrocarbon radicals; octadecylamine hydrochloride is one of the         cationic surfactants which can be used,     -   non-ionic surfactants, such as optionally polyoxyethylenated         esters of sorbitan, in particular Polysorbate 80, or         polyoxyethylenated alkyl ethers; polyethylene glycol stearate,         polyoxyethylenated derivatives of castor oil, polyglycerol         esters, polyoxyethylenated fatty alcohols, polyoxyethylenated         fatty acids or copolymers of ethylene oxide and of propylene         oxide,     -   amphoteric surfactants, such as substituted lauryl compounds of         betaine,     -   or preferably a mixture of at least two of the compounds listed         above.

In a particular preferred embodiment, a crystallization inhibitor pair will be used. Such pairs include, for example, the combination of a film-forming agent of polymeric type and of a surface-active agent. These agents will be selected in particular from the compounds mentioned above as crystallization inhibitors.

Particularly preferred film-forming agents of polymeric type include:

-   -   the various grades of polyvinylpyrrolidone,     -   polyvinyl alcohols, and     -   copolymers of vinyl acetate and of vinylpyrrolidone.

Especially preferred surface-active agents, include those made of non-ionic surfactants, preferably polyoxyethylenated esters of sorbitan and in particular the various grades of polysorbate, for example Polysorbate 80.

The film-forming agent and the surface-active agent can in particular be incorporated in similar or identical amounts within the limit of the total amounts of crystallization inhibitor mentioned elsewhere.

The pair thus constituted secures, in a noteworthy way, the objectives of absence of crystallization on the coat and of maintenance of the cosmetic appearance of the fur, that is to say without a tendency towards sticking or towards a sticky appearance, despite the high concentration of active material.

Particularly preferred antioxidizing agents are those conventional in the art and include, for example, butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate or a mixture of not more than two of them.

The formulation adjuvants discussed above are well known to the practitioner in this art and may be obtained commercially or through known techniques. These concentrated compositions are generally prepared by simple mixing of the constituents as defined above; advantageously, the starting point is to mix the active material in the main solvent and then the other ingredients or adjuvants are added.

The determination of an effective amount of a given therapeutic agent would be well known to the practitioner since many the individual agents an combinations containing these agents are known. For example, the amount of 1-N-arylpyrazole for birds and animals which are small in size is preferably greater than about 0.01 mg and in a particularly preferred way between about 1 and about 50 mg/kg of weight of animal. For topical combinations comprising 1-N-arylpyrazoles and IGR's it is preferable to administer to the animal a dose of from about 0.1 to about 40 and in particular from about 1 to about 20 mg/kg of 1-N-phenylpyrazole and a dose of from about 0.1 to about 40 and in particular about 1 to about 30 mg/kg of IGR compound. Preferred doses are from about 5 to about 15 mg/kg of 1-N-arylpyrazoles and from about 0.5 to about 15 mg/kg for the preferred IGR compounds, or about 10 to about 20 mg/kg for the other IGR compounds.

For spot-on or pour-on formulations, the N-arylpyrazoles can advantageously be present in the formulations in a proportion of about 1 to about 20%, preferably of about 5 to about 15% (percentages as weight by volume=W/V). The liquid carrier vehicle comprises a pharmaceutically or veterinary acceptable organic solvent and optionally an organic cosolvent.

The volume applied can be of the order of about 0.3 to about 1 ml, preferably of the order of about 0.5 ml, for cats and of the order of about 0.3 to about 3 ml for dogs, depending on the weight of the animal.

For nodulisporic acid derivatives, generally a dose of from about 0.001 to about 100 mg per kg of body weight, with a range of 0.25 to 50 mg/kg being especially preferred, given as a single dose or in divided doses for a period of from about 1 to about 60 days, preferably from about 1 to 30 days.

Preferred amounts of anthelmintic agents such as praziquantel or morantel include, for example, from about 0.5 mg/kg to about 7.5 mg/kg of animal body weight, with a range of about 0.5 mg/kg to about 2 mg/kg or 2.5 mg/kg of body weight being especially preferred. A most especially preferred amount is about 1.0 mg/kg of animal body weight. Preferred ranges for the macrolide compounds include, for example about 0.01 to about 200 mg/kg of animal body weight, with the ranges of about 0.1 to about 50 mg/kg and from about 1 to about 30 mg/kg being especially preferred.

Having thus described in detail preferred embodiments of the present invention, it is to be understood that the invention defined by the appended claims is not to be limited to particular details set forth in the above description as many apparent variations thereof are possible without departing from the spirit or scope of the present invention. 

1. A liquid agent applicator comprising: a collapsible reservoir for storing the liquid agent; a shaft having a lumen there through connected to said collapsible reservoir; an opening mechanism inserted into an orifice formed in one end of said shaft; and a breakable seal formed between said opening mechanism and said shaft, wherein twisting of said opening mechanism relative to said shaft breaks said seal allowing egress of the liquid agent stored in said reservoir.
 2. The liquid applicator of claim 1, wherein said seal is formed by thermoforming.
 3. The liquid applicator of claim 1, wherein said seal is formed between the opening mechanism and an interior surface of said shaft.
 4. The liquid applicator of claim 1, wherein said seal is formed by matching threads formed on said opening mechanism and said shaft.
 5. The liquid applicator of claim 1, wherein said seal is formed by the elastic properties of said shaft conforming to the shape of said opening mechanism inserted therein.
 6. The liquid applicator of claim 1, further comprising grips formed on said reservoir.
 7. The liquid applicator of claim 1, further comprising a flat base.
 8. The liquid applicator of claim 1, wherein said reservoir is formed by thermoforming one or more sheets of plastic material.
 9. The liquid applicator of claim 1, formed of a chemically compatible material for use with anti-flea and tick agents.
 10. The liquid applicator of claim 1, wherein said opening mechanism is child resistant.
 11. The liquid applicator of claim 10, wherein the child resistant opening mechanism comprises: a rigid stationary neck; a movable cap; a septum for preventing the egress of liquid from said reservoir formed on said stationary neck; a punch formed on said movable cap, for piercing said septum to allow the egress of liquid from said reservoir; and an interlock requiring two or more movements of said movable cap by the user, wherein upon completion of said two or more actions, said movable cover is movable along said stationary neck in the direction of said septum, the movement of said movable cap causing said punch to pierce the septum.
 12. The liquid agent applicator of claim 1 wherein the liquid agent is topical pharmaceutical or veterinary formulation.
 13. The liquid agent applicator of claim 1, wherein the applicator is formed poly acrylo nitrile. 